Cell Cycle

Deregulation of cell cycle control proteins plays a key role in the development of cancer. Overactivation of proteins that favor cell cycle progression, namely cyclins and CDKs, and the inactivation of proteins that impede cell cycle progression, such as CKIs, can result in uncontrolled cell proliferation.

In human tumors, it is genes encoding the proteins that control the transition from the G₁ to the S phase that are most commonly altered. These genes include those for cyclins, CKIs, and pRb. Such mutations overcome the inhibitory effects of pRb on the cell cycle, causing cells to have a growth advantage. In some cancers, this occurs after the direct mutation of the pRb gene, resulting in the protein's loss of function. In a larger set of cancers, pRb is indirectly inactivated by the hyper-activation of CDKs. This may result from over expression of cyclins, from an activating mutation in CDK4, or from inactivation of CKIs.

There is much evidence to suggest that cyclins can act as oncogenes to induce cells to become cancerous. In particular the G₁ cyclins, cyclin D1, and cyclin E have been implicated in the development of cancer. Over-expression of the cyclin D1 protein is frequently detected in human breast cancer, and increasing evidence suggests that cyclin E overexpression plays an important role in the pathogenesis of breast cancer.

CKIs antagonize the function of cyclins, and considerable evidence suggests that these proteins function as tumor suppressors. CKI function is often altered in cancer cells. The gene encoding p16, a protein that belongs to the INK family of CKIs, is mutated, deleted, or inactivated in a large number of human malignancies and tumors. Such alterations prevent the inhibition of cyclin D/CDK4 and cyclin D/CDK6 complexes during G₁.

Decreased expression of p21 and p27, proteins that belong to the Cip/Kip family of CKIs, also has been demonstrated in numerous human tumors. In contrast to the genetic mutations observed with p16, the decrease in p27 levels in tumors is due to enhanced degradation of the p27 protein. One of the proteins required for the degradation of p27, Skp2, has oncogenic properties. Skp2 over expression is observed in several human cancers and likely contributes to the uncontrolled progression of the cell cycle by increasing the degradation of p27. Understanding of the fine details of cell cycle regulation is likely to lead to specific cancer therapies targeting one or more of these important proteins.